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Alexander V Kulikov, Raul R Gainetdinov, Evgeni Ponimaskin, Allan V Kalueff, Vladimir S Naumenko, Nina K Popova
Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3-4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs. Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance...
March 15, 2018: Expert Opinion on Therapeutic Targets
D A Nikishin, N M Alyoshina, Y B Shmukler
Using RT-PCR, we showed the presence of Tph1 mRNA in follicular cells and Tph2 mRNA in oocytes isolated from primary multilayer ovarian follicles of mouse and the absence of Ddc expression, which indicates that serotonin cannot be synthesized in a developing ovarian follicle. The membrane serotonin transporter Sert is expressed in follicular cells and oocytes. Experiments on the cultivation of follicles in vitro confirmed the absence of serotonin synthesis from 5-hydroxytryptophan and the presence of membrane transport activity in the oocyte...
January 2018: Doklady. Biochemistry and Biophysics
Tanja Scherer, Gabriella Allegri, Christineh N Sarkissian, Ming Ying, Hiu Man Grisch-Chan, Anahita Rassi, Shelley R Winn, Cary O Harding, Aurora Martinez, Beat Thöny
Hyperphenylalaninemia (HPA) caused by hepatic phenylalanine hydroxylase (PAH) deficiency has severe consequences on brain monoamine neurotransmitter metabolism. We have studied monoamine neurotransmitter status and the effect of tetrahydrobiopterin (BH4 ) treatment in Pahenu1/enu2 (ENU1/2) mice, a model of partial PAH deficiency. These mice exhibit elevated blood L-phenylalanine (L-Phe) concentrations similar to that of mild hyperphenylalaninemia (HPA), but brain levels of L-Phe are still ~5-fold elevated compared to wild-type...
March 8, 2018: Journal of Inherited Metabolic Disease
Nina C Donner, Kenneth H Kubala, James E Hassell, Margaret W Lieb, Kadi T Nguyen, Jared D Heinze, Robert C Drugan, Steven F Maier, Christopher A Lowry
Expression of TPH2, the rate-limiting enzyme for brain serotonin synthesis, is elevated in the dorsal raphe nucleus (DR) of depressed suicide victims. One hypothesis is that this increase in TPH2 expression is stress-induced. Here, we used an established animal model to address whether exposure to an acute stressor, inescapable tail shock (IS), increases tph2 mRNA and Tph2 protein expression, and if IS sensitizes the DR to a subsequent, heterotypic stressor. In Experiment 1 , we measured tph2 mRNA expression 4 h after IS or home cage (HC) control conditions in male rats, using in situ hybridization histochemistry...
February 2018: Neurobiology of Stress
Mihye Ko, Smi Choi-Kwon, Sang-Eun Jun, Ju Han Kim, Kyung-Hee Cho, Hyun-Wook Nah, Hasup Song, Jong S Kim
Objectives: Emotional dysfunction is a common finding in stroke patients. Despite reports on serotonergic involvement in the etiology of poststroke emotional dysfunction (PSED), the role of serotonin synthesizing tryptophan hydroxylase 2 (TPH2) genes in the development of PSED remains unclear. Methods: Genotyping of TPH2 rs4641528 and rs10879355 was performed from genomic DNA of 383 stroke patients collected previously and stored at -70°C. Potential associations between TPH 2 genes and poststroke depression (PSD), poststroke emotional incontinence (PSEI), and poststroke anger proneness (PSAP) were investigated 3 months poststroke...
February 2018: Brain and Behavior
Ying Huo, Yaohua Zhang, Huifen Guo, Yingjuan Liu, Qi Fang, Jianxu Zhang
The central 5-hydroxytryptamine system impairs sociosexual behaviors and olfaction preferences in sexually naive mice. However, it remains unknown whether reproductive experiences impart an effect on the sexual olfactory preferences of female mice lacking central serotonin. Here, we aimed at examining such effects and the underlying mechanisms using Tph2 knockout female mice. Sexually naive Tph2-/- female mice failed to recognize olfactory cues regarding sex, genetic relatedness, and social hierarchy despite exhibiting normal olfactory discrimination...
2018: PloS One
Feng Wang, Mingliang Fang, David E Hinton, Melissa Chernick, Shenglan Jia, Yingdan Zhang, Lingtian Xie, Wenjing Dong, Wu Dong
Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants that are ubiquitously detected in the environment and associated with adverse health outcomes. 6-OH-BDE-47 is a metabolite of the flame retardant, 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), and there is increasing concern regarding its developmental neurotoxicity and endocrine disrupting properties. In this study, we report that early life exposure in zebrafish (Danio rerio) embryos to 6-OH-BDE-47 (50 and 100 nM) resulted in higher coiling frequency and significantly increased apoptotic cells in the brain...
February 3, 2018: Chemosphere
J H Piel, T A Lett, C Wackerhagen, M M Plichta, S Mohnke, O Grimm, N Romanczuk-Seiferth, F Degenhardt, H Tost, S Witt, M Nöthen, M Rietschel, A Heinz, A Meyer-Lindenberg, H Walter, S Erk
Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition...
March 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Shelley R Winn, Tanja Scherer, Beat Thöny, Ming Ying, Aurora Martinez, Sydney Weber, Jacob Raber, Cary O Harding
Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice...
January 2018: Molecular Genetics and Metabolism
Paulina Wigner, Piotr Czarny, Ewelina Synowiec, Michał Bijak, Katarzyna Białek, Monika Talarowska, Piotr Galecki, Janusz Szemraj, Tomasz Sliwinski
Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804-7C>A (rs10488682), c.-1668T>A (rs623580), c.803+221C>A (rs1800532), c.-173A>T (rs1799913)-TPH1, c...
January 5, 2018: Journal of Cellular and Molecular Medicine
Melanie Y Vincent, Nina C Donner, David G Smith, Christopher A Lowry, Lauren Jacobson
The serotonergic dorsal raphé nucleus (DRN) expresses glucocorticoid receptors (GR), and systemic glucocorticoids have been shown to regulate expression and activity of tryptophan hydroxylase isoform 2, the rate-limiting enzyme for serotonin synthesis in brain. We have used intra-DRN injection of pseudotyped adeno-associated virus AAV2/9 transducing either green fluorescent protein (GFP control) or Cre recombinase (DRN GR deletion) in floxed GR mice to determine if DRN GR directly regulate DRN mRNA levels of tryptophan hydroxylase 2 (tph2)...
February 5, 2018: Neuroscience Letters
Boris Mlinar, Alberto Montalbano, Jonas Waider, Klaus-Peter Lesch, Renato Corradetti
Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT1A autoreceptors (5-HT1A ARs). Enhanced 5-HT1A AR functioning may cause decreased serotonergic signaling in brain and has thereby been implicated in the etiology of mood and anxiety disorders. Tryptophan hydroxylase-2 knockout (Tph2-/- ) mice exhibit sensitization of 5-HT1A agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HT1A AR functioning. To elucidate the mechanisms underlying 5-HT1A AR supersensitivity in Tph2-/- mice, we characterized the activation of G protein-coupled inwardly-rectifying potassium (GIRK) conductance by the 5-HT1A receptor agonist 5-carboxamidotryptamine using whole-cell recordings from serotonergic neurons in dorsal raphe nucleus...
December 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Jennifer L Magnusson, Kevin James Cummings
Sudden Infant Death Syndrome (SIDS) is associated with serotonin (5-HT) neuron abnormalities. There is evidence of autonomic dysfunction during sleep in infants eventually succumbing to SIDS, as well as cardiovascular collapse prior to death. Neonatal rodents deficient in central 5-HT display hypotension and bradycardia. We hypothesized that central 5-HT reduces cardiac vagal tone and increases sympathetic vascular tone and, given the firing pattern of 5-HT neurons, that these effects are greater in quiet sleep (QS) than in active sleep (AS)...
October 18, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Kasper D Tidemand, Günther H Peters, Pernille Harris, Eva Stensgaard, Hans E M Christensen
Tryptophan hydroxylase (TPH) catalyzes the initial and rate-limiting step in the biosynthesis of serotonin, which is associated with a variety of disorders such as depression and irritable bowel syndrome. TPH exists in two isoforms: TPH1 and TPH2. TPH1 catalyzes the initial step in the synthesis of serotonin in the peripheral tissues, while TPH2 catalyzes this step in the brain. In this study, the steady-state kinetic mechanism for the catalytic domain of human TPH1 has been determined. Varying substrate tryptophan (Trp) and tetrahydrobiopterin (BH4) results in a hybrid Ping Pong-ordered mechanism in which the reaction can either occur through a Ping Pong or a sequential mechanism depending on the concentration of tryptophan...
October 27, 2017: Biochemistry
J Waider, S Popp, M D Lange, R Kern, J F Kolter, J Kobler, N C Donner, K R Lowe, J H Malzbender, C J Brazell, M R Arnold, B Aboagye, A Schmitt-Böhrer, C A Lowry, H C Pape, K P Lesch
Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings...
October 3, 2017: Translational Psychiatry
Yi Chen, Haixia Xu, Mingyue Zhu, Kun Liu, Bo Lin, Ruxian Luo, Chuanbai Chen, Mengsen Li
Serotonin (5-hydroxytryptamine, 5-HT) dysfunction is associated with the pathophysiology of depression. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis, is believed to have essential role in many mental disorders, including depression. In the present study, we generated a rat model of depression by exposing the animals to stress, and the rats were then treated with paroxetine. The results indicated that the concentration of 5-HT in the brain and liver tissues were significantly lower in the rat model of depression than in healthy or treated rats...
September 8, 2017: Oncotarget
Satoshi Ansai, Hiroshi Hosokawa, Shingo Maegawa, Kiyoshi Naruse, Youhei Washio, Kenji Sato, Masato Kinoshita
Serotonin (5-hydroxytryptamine [5-HT]) is a bioactive monoamine that acts as a neurotransmitter in the central and peripheral nervous system of animals. Teleost fish species have serotonergic neurons in the raphe nuclei of the brainstem; however, the role of 5-HT in the raphe neurons in teleost fish remains largely unknown. Here, we established a medaka (Oryzias latipes) strain with targeted disruption of tryptophan hydroxylase 2 (tph2) gene that is involved in the 5-HT synthesis in the raphe nuclei. Immunohistochemistry and mass spectrometry analysis revealed that the homozygous mutants (tph2Δ13/Δ13 ) lacked the ability to synthesize 5-HT in the raphe neurons...
December 2017: Zebrafish
Bojan Mirkovic, David Cohen, Claudine Laurent, Malaika Lasfar, Christophe Marguet, Prsicille Gerardin
Background Suicide is the second leading cause of death for 10-19-year-olds. Evidence has shown that attempted suicide is a complex interplay of genes and environmental factors. In the adult population, possible associations between genetic polymorphisms and suicidal behaviors have been investigated for several genes, most often with inconsistent findings and poor replicability of significant associations. This study aimed to identify gene variants conferring risk for adolescent suicide attempt. Methods We selected the genes and variants after an analysis of the literature and a selection of the most significant associations identified...
September 13, 2017: International Journal of Adolescent Medicine and Health
James H Fox, James E Hassell, Philip H Siebler, Mathew R Arnold, Andrew K Lamb, David G Smith, Heidi E W Day, Tessa M Smith, Emma M Simmerman, Alexander A Outzen, Kaley S Holmes, Christopher J Brazell, Christopher A Lowry
The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits, and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for trauma-related, anxiety, and affective disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience...
September 6, 2017: Brain, Behavior, and Immunity
Ze Li, Hai-Yuan Yang, Ying Wang, Man-Ling Zhang, Xiao-Rui Liu, Qiang Xiong, Li-Ning Zhang, Yong Jin, Li-Sha Mou, Yan Liu, Rong-Feng Li, Yi Rao, Yi-Fan Dai
Unbalanced brain serotonin (5-HT) levels have implications in various behavioral abnormalities and neuropsychiatric disorders. The biosynthesis of neuronal 5-HT is regulated by the rate-limiting enzyme, tryptophan hydroxylase-2 (TPH2). In the present study, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system was used to target theTph2 gene in Bama mini pig fetal fibroblasts. It was found that CRISPR/Cas9 targeting efficiency could be as high as 61.5%, and the biallelic mutation efficiency reached at 38...
September 26, 2017: Journal of Biomedical Research
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